Paraquat dichloride (methyl viologen; PQ) is an effective and widely used herbicide that has a proven safety record when appropriately applied to eliminate weeds. However, over the last decades, there have been numerous fatalities, mainly caused by accidental or voluntary ingestion. PQ poisoning is an extremely frustrating condition to manage clinically, due to the elevated morbidity and mortality observed so far and due to the lack of effective treatments to be used in humans. PQ mainly accumulates in the lung (pulmonary concentrations can be 6 to 10 times higher than those in the plasma), where it is retained even when blood levels start to decrease. The pulmonary effects can be explained by the participation of the polyamine transport system abundantly expressed in the membrane of alveolar cells type I, II, and Clara cells. Further downstream at the toxicodynamic level, the main molecular mechanism of PQ toxicity is based on redox cycling and intracellular oxidative stress generation. With this review we aimed to collect and describe the most pertinent and significant findings published in established scientific publications since the discovery of PQ, focusing on the most recent developments related to PQ lung toxicity and their relevance to the treatment of human poisonings. Considerable space is also dedicated to techniques for prognosis prediction, since these could allow development of rigorous clinical protocols that may produce comparable data for the evaluation of proposed therapies.

Repeated pulse of methylprednisolone and cyclophosphamide with continuous dexamethasone therapy for patients with severe paraquat poisoning.

OBJECTIVE: Paraquat is widely used in the world, and all treatments for paraquat poisoning have been unsuccessful. Many patients have died of paraquat poisoning in developing countries. A novel anti-inflammation method was developed to treat severe paraquat-poisoned patients with >50% to <90% predictive mortality: initial pulse therapy with methylprednisolone (1 g/day for 3 days) and cyclophosphamide (15 mg/kg/day for 2 days), followed by dexamethasone 20 mg/day until Pao2 was >11.5 kPa (80 mm Hg) and repeated pulse therapy with methylprednisolone (1 g/day for 3 days) and cyclophosphamide (15 mg/kg/day for 1 day), which was repeated if Pao2 was <8.64 kPa (60 mm Hg).

PATIENTS: Twenty-three paraquat-poisoned patients with >50% and <90% predictive mortality assessed by plasma paraquat levels were prospectively and randomly assigned to the control and study groups at a proportion of 1:2.

INTERVENTIONS: The control group received conventional therapy and the study group received the novel repeated pulse treatment with long-term steroid therapy.

MEASUREMENTS AND MAIN RESULTS: We measured patient mortality during the study period. There was not a different distribution of basal variables between the two study groups. The mortality rate (85.7%, six of seven) of the control group was higher than that of the study group (31.3%, five of 16; p = .0272).

Mercury in both organic and inorganic forms is neurotoxic. Methylmercury (MeHg) is a commonly encountered form of mercury in the environment. Early electrophysiological experiments revealed that MeHg potently affects the release of neurotransmitter from presynaptic nerve terminals. Recently, the hypothesis that these alterations may be mediated by changes in the intracellular concentration of Ca2+ ([Ca2+]i) has been supported. MeHg alters [Ca2+]i by at least two mechanisms. First, it disrupts regulation of Ca2+ from an intracellular Ca2+ pool and second, it increases the permeability of the plasma membrane to Ca2+. MeHg also blocks plasma membrane voltage-dependent Ca2+ and Na+ channels in addition to activating a nonspecific transmembrane cation conductance. Chronic MeHg exposure results in ultrastructural changes and accumulation of MeHg within mitochondria. In vitro, MeHg inhibits several mitochondrial enzymes and depolarizes the mitochondria membrane subsequently reducing ATP production and Ca2+ buffering capacity. Inhibition of protein synthesis is observed after in vivo or in vitro exposures of MeHg and may be an early effect of MeHg. Thus, the early cellular effects of exposure to MeHg are diverse and cell damage likely occurs by more than one mechanism, the effects of which may be additive or synergistic.

Mercury in both organic and inorganic forms is neurotoxic. Methylmercury (MeHg) is a commonly encountered form of mercury in the environment. Early electrophysiological experiments revealed that MeHg potently affects the release of neurotransmitter from presynaptic nerve terminals. Recently, the hypothesis that these alterations may be mediated by changes in the intracellular concentration of Ca2+ ([Ca2+]i) has been supported. MeHg alters [Ca2+]i by at least two mechanisms. First, it disrupts regulation of Ca2+ from an intracellular Ca2+ pool and second, it increases the permeability of the plasma membrane to Ca2+. MeHg also blocks plasma membrane voltage-dependent Ca2+ and Na+ channels in addition to activating a nonspecific transmembrane cation conductance. Chronic MeHg exposure results in ultrastructural changes and accumulation of MeHg within mitochondria. In vitro, MeHg inhibits several mitochondrial enzymes and depolarizes the mitochondria membrane subsequently reducing ATP production and Ca2+ buffering capacity. Inhibition of protein synthesis is observed after in vivo or in vitro exposures of MeHg and may be an early effect of MeHg. Thus, the early cellular effects of exposure to MeHg are diverse and cell damage likely occurs by more than one mechanism, the effects of which may be additive or synergistic.

In another example , a professor doing lab research was accidentally exposed to a some drops of dimethylmercury on the back of her gloved hand. This organic mercury diffused into the glove and then got absorbed by the woman. After 3 months she began experiencing episodes of nausea, diarrhea, and abdominal discomfort. During the next 2 months she also began losing weight. At the end of 5 months she began to lose speech, balance, and the ability to walk. In the following days the woman noted "tingling in her fingers, brief flashes of light in both eyes, a soft background noise in both ears, and progressive difficulty with speech, walking, hearing, and vision (constricted visual fields)". Her blood mercury level was tested and found to be 500x to 4000x higher than expected. Oral chelation was started, but neurodegeneration continued. Blood exchange transfusion didn't work because too much mercury was already in her body tissue. By 6 months after exposure the woman became unresponsive to all visual, verbal, and light-touch stimuli. She had "periods of spontaneous eye opening, but without awareness". She exhibited spontaneous "yawning, moaning, and limb movements", with "periods of agitation and crying". The woman fell into a coma. Almost 10 months after exposure the woman was removed from life-support (per her advanced directives) and died.

Quicksilver (liquid metallic mercury) is poorly absorbed by ingestion and skin contact. It is hazardous due to its potential to release mercury vapour. Animal data indicate that less than 0.01% of ingested mercury is absorbed through the intact gastrointestinal tract; though it may not be true for individuals suffering from ileus. Cases of systemic toxicity from accidental swallowing are rare, and attempted suicide via intravenous injection does not appear to result in systemic toxicity. Though not studied quantitatively, the physical properties of liquid elemental mercury limit its absorption through intact skin and in light of its very low absorption rate from the gastrointestinal tract, skin absorption would not be high. Some mercury vapour is absorbed dermally but uptake by this route is only approximately 1% of that by inhalation.

In humans, approximately 80% of inhaled mercury vapour is absorbed via the respiratory tract where it enters the circulatory system and is distributed throughout the body. Chronic exposure by inhalation, even at low concentrations in the range 0.7–42 μg/m3, has been shown in case control studies to cause effects such as tremors, impaired cognitive skills, and sleep disturbance in workers.

Inorganic mercury compounds

Mercury occurs inorganically as salts such as mercury(II) chloride. Mercury salts primarily affect the gastro-intestinal tract and the kidneys, and can cause severe kidney damage; however, as they can not cross the blood-brain barrier easily, mercury salts inflict little neurological damage without continuous or heavy exposure. As two oxidation states of mercury form salts (Hg+ and Hg2+), mercury salts occur in both mercury(I) (or mercurous) and mercury(II) (mercuric) forms. Mercury(II) salts are usually more toxic than their mercury(I) counterparts because their solubility in water is greater; thus, they are more readily absorbed from the gastrointestinal tract.

Organic mercury compounds

Compounds of mercury tend to be much more toxic than the element itself, and organic compounds of mercury are often extremely toxic and have been implicated in causing brain and liver damage. The most dangerous mercury compound, dimethylmercury, is so toxic that even a few microliters spilled on the skin, or even a latex glove, can cause death.

Methylmercury is the major source of organic mercury for all individuals. It works its way up the food chain through bioaccumulation in the environment, reaching high concentrations among populations of some species. Larger species of fish, such as tuna or swordfish, are usually of greater concern than smaller species. The U.S. Food and Drug Administration (FDA) and the U.S. Environmental Protection Agency (EPA) advise women of child-bearing age, nursing mothers, and young children to completely avoid swordfish, shark, king mackerel and tilefish (golden bass), to limit consumption of albacore ("white") tuna to no more than 6 oz (170 g) per week, and of all other fish and shellfish to no more than 12 oz (340 g) per week. A 2006 review of the risks and benefits of fish consumption found that for adults the benefits of one to two servings of fish per week outweigh the risks, even (except for a few fish species) for women of childbearing age, and that avoidance of fish consumption could result in significant excess coronary heart disease deaths and suboptimal neural development in children.

Ethylmercury is a breakdown product of the antibacteriological agent ethylmercurithiosalicylate, which has been used as a topical antiseptic and a vaccine preservative (further discussed under Thiomersal below). Its characteristics have not been studied as extensively as methylmercury. It is cleared from the blood much more rapidly, with a half-life of 7 to 10 days, and it is metabolized much more quickly than methylmercury. It probably does not have methylmercury's ability to cross the blood-brain barrier via a transporter, but instead relies on simple diffusion to enter the brain.

Other exposure sources of organic mercury include phenylmercuric acetate and phenylmercuric nitrate. These were used in indoor latex paints for their anti-mildew properties, but were removed in 1990 because of cases of toxicity.

In another example , a professor doing lab research was accidentally exposed to a some drops of dimethylmercury on the back of her gloved hand. This organic mercury diffused into the glove and then got absorbed by the woman. After 3 months she began experiencing episodes of nausea, diarrhea, and abdominal discomfort. During the next 2 months she also began losing weight. At the end of 5 months she began to lose speech, balance, and the ability to walk. In the following days the woman noted "tingling in her fingers, brief flashes of light in both eyes, a soft background noise in both ears, and progressive difficulty with speech, walking, hearing, and vision (constricted visual fields)". Her blood mercury level was tested and found to be 500x to 4000x higher than expected. Oral chelation was started, but neurodegeneration continued. Blood exchange transfusion didn't work because too much mercury was already in her body tissue. By 6 months after exposure the woman became unresponsive to all visual, verbal, and light-touch stimuli. She had "periods of spontaneous eye opening, but without awareness". She exhibited spontaneous "yawning, moaning, and limb movements", with "periods of agitation and crying". The woman fell into a coma. Almost 10 months after exposure the woman was removed from life-support (per her advanced directives) and died.